Abstract

B230

The receptor tyrosine kinase (RTK), Axl, is a novel therapeutic target for solid tumors. Axl is expressed in both neoplastic and stromal compartments and is associated with poor outcome in several human tumor types. Signaling via Axl drives proliferation, migration and invasion and protects cells from apoptosis. Genetic inhibition of Axl signaling both blocks tumor growth and suppresses angiogenesis in vivo. These data suggest that Axl inhibitors may suppress tumor growth via multiple mechanisms. By high throughput screening of a diverse chemical library followed by an extensive structure activity relationship (SAR) study, we have identified small molecule inhibitors of Axl kinase which exhibit potent on-target activity in both cell-based and biochemical assays. The compounds fall into two classes: 1) those that potently block Axl and VEGFR2 signaling but are selective over other RTKs including EGFR and InsulinR, and 2) Axl-selective inhibitors. Both classes of compound inhibit the proliferation of sensitive tumor cell lines in vitro but lack potent generalized antiproliferative activity. Rigel’s Axl inhibitors demonstrate favorable pharmacokinetic properties and are generally well tolerated. Our lead Axl / VEGFR2 inhibitor potently blocked bFGF-induced angiogenesis in a corneal micropocket assay (p< 0.001). This compound also strongly inhibited the growth of three different tumor cell lines in vivo in subcutaneous murine xenograft models and was able to extend survival of tumored animals. Regressions were noted in one study. Importantly, our lead Axl-selective inhibitor also significantly reduced corneal neovascularization (p< 0.001). Furthermore, partial suppression of tumor growth in vivo was also observed with this compound. Rigel has generated potent and selective inhibitors of Axl kinase. We propose that small molecule inhibition of Axl represents a novel therapy for a subgroup of sensitive solid tumors.